Pharmacokinetic/Pharmacodynamic (PK/PD) Studies of Methylphenidate Extended Release Products in Pediatric Attention Deficit Hyperactivity Disorder (ADHD) (U01) Summary/Abstract We propose to conduct a prospective pharmacokinetic (PK)/pharmacodynamic (PD) study of long acting methylphenidate (MPH) formulations in pediatric ADHD patients to examine novel PK parameters beyond AUC and Cmax, traditionally used to determine generic equivalency. Long acting MPH formulations considered equivalent by PK (AUC and Cmax) were shown to be significantly different in PD for onset, midday effectiveness as well as offset. To address these limitations, we propose to test the PK/PD relationship of MPH in three distinct PK profiles (shapes): 1) gradual onset with ascending kinetics (OROS);2) rapid onset with biphasic pulse delivery kinetics (two peaks and troughs;Ritalin LA);3) rapid onset with one pulse delivery kinetics (one peak;Quillivant XR). In each model, we will separately assess the initial (onset), middle and terminal (offset) portions of the PK/PD relationship as assessed through an analogue laboratory classroom methodology. A diseasedrugtrial model paradigm will be applied to the data to integrate MPH PK findings, covariates, time course of clinical outcomes, placebo effects, drug's pharmacologic effects, and trial execution characteristics. This approach will provide guidance for the evaluation of the impact of different concentration- time profiles on the PD effect of MPH extended release products (1). A population PK/PD model will be developed using individual observations collected in the target pediatric population to explain the drug response accounting for the placebo effect and for the time varying response of MPH (tachyphylaxis). A previously developed PK/PD model (2) was implemented using a meta-analytic approach using mean data extracted from published papers. This model was able to predict pediatric PD [both math tests (PERMP) and behavioral ratings (SKAMP)] from adult PK data. To improve upon limitations of this model, we propose to generalize the model by using pediatric PK instead of adult PK and, most importantly, to use individual PK and PD measurements rather than relying on mean observations as well as to separately address onset, midday and offset. Our overarching objective is to provide a validated model appropriate for predicting, with a known uncertainty level, the impact of a given PK profile on the therapeutic equivalence of MPH extended release products. The findings from this proposed novel PK/PD study will help establish scientific and regulatory standards for assuring therapeutic equivalence of generic methylphenidate extended release products.

Public Health Relevance

Our overarching objective is to provide a validated pharmacokinetic (PK) / pharmacodynamic (PD) model appropriate for predicting, with a known uncertainty level, the impact of a given PK profile on the therapeutic equivalence of MPH extended release products as measured through analogue laboratory classroom methodology. The findings from this proposed novel PK/PD study will help establish scientific and regulatory standards for assuring therapeutic equivalence of generic methylphenidate extended release products.